Four major antiepileptic drugs (AEDs) are used for the treatment of epilepsy (epileptic seizures and convulsions): phenytoin, carbamazepine, phenobarbital and valproic acid (VPA). However, about 25% of the patients do not respond to the current medications. Furthermore, AEDs are administered repetitively as chronic treatment and the adverse effects associated with antiepileptic therapy are of a major concern. The major established AEDs are associated with some rare but severe side effect such as teratogenicity. In addition, all the AEDs have other adverse effects that limit their use. Valproic acid itself has considerable adverse effects including fatal hepatotoxicity.
One approach to obtain improved antiepileptic agents has been to prepare the primary amide derivatives of valproic acid and its analogs. Valnoctamide (VCD) and propyl-isoproylacetamide (PID) are analogous of the amide derivative of valproic acid, valpromide (VPD). They have improved anticonvulsant activity when compared to VPA. These amide analogues of valproic acid have been shown to be non-teratogenic, O. Spiegelstein, M. Bialer, M. Radatz, H. Nau and B. Yagen Chirality, 11:645–650 (1999).
Amide derivatives of tetramethylcyclopropane carboxylic acid have also been previously evaluated for their anticonvulsant activity (M. Bialer, S. Hadad, B. Kadry, A. Abdul-Hai, A. Haj-Yehia, J. Sterling, Y. Herzig and B. Yagen Pharm Res. 13:284–289 (1996); J. Sterling, et al. U.S. Pat. No. 5,880,157, issued March. 1999; N. Isoherranen et al, Epilepsy 43: 115–126 (2002)). These derivatives had good anticonvulsant activity and superior brain penetration than VPA. The N-methyl-tetramethylcyclopropyl carboxamide has a wide spectrum of anticonvulsant activity and is approximately 10 times more potent than VPA in animal models of epilepsy. In addition, N-methyl-tetramethylcyclopropane carboxamide and tetramethylcyclopropane carboxamide were not teratogenic in mouse model.
Currently 25% of epileptic patients are not seizure free with existing medications and thus are considered as therapy resistant or refractory epileptic patients.
Thus, there is still a substantial need for new anti epileptic and central nervous system (CNS) drugs that will be effective in refractory epileptic patients.
Furthermore, an urgent need still exists in the art for anti epileptic agents with an improved efficacy and a wider margin between the dose which is therapeutic and that which is neurotoxic.
Additionally, it would be highly advantageous to have new compounds effective against pain, psychotic disorders and neurodegenerative diseases.